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Colorectal carcinoma (CRC) is associated with significant morbidity and mortality worldwide. Cytokeratins (CKs) are widely expressed in various types of carcinomas, whereas in CRC it is usually CK7 − and CK20 + . A subset of CRCs is CK7 + . This study aims to determine the prevalence of CK7 expression in CRC and its impact on overall survival. We analyzed 300 randomly selected surgically treated CRC cases using paraffin embedded tumor tissue samples and evaluated CK7 and CK20 expression using the tissue microarray method. Tumors with positivity > 10% and > 25% of tumor cells were considered CK7 and CK20 positive, respectively. Expression of both CKs and several clinical-pathological variables (stage, grade, laterality, mismatch-repair/MMR status) were evaluated using patient follow up data (Kaplan–Meier analysis of cancer-specific survival (CSS)). Significant results include shorter CSS (restricted mean 4.98 vs. 7.74 years, P  = 0.007) and 5-year survival (29.4% vs. 64.6%, P  = 0.0221) in CK7 + tumors compared to CK7 − tumors, respectively; without significant association with grade, stage or right-sided location. These results were significant in a multivariate analysis. CK20 + tumors are more frequently MMR-proficient and left-sided. MMR-deficient tumors are more frequently right-sided and had longer survival. CK7 expression, right-sided location (rmean CSS 6.83 vs. 8.0 years, P  = 0.043), MMR-proficiency (rmean CSS 7.41 vs. 9.32 years, P  = 0.012), and UICC stages III + IV (rmean CSS 6.03 vs. 8.92 years, P  < 0.001) of the tumor correlated with negative prognostic outcomes, whereas the most significant results concern stage and CK7 positivity. The result concerning negative prognostic role of CK7 differs from those obtained by several previous studies focused on this topic.

The type and extent of histological changes after acute electrical injury are a matter of interest and debate. To investigate the acute changes associated with electric current, we used an animal model consisting of 21 healthy adult male and female New Zealand White conventionally bred domestic rabbits (Oryctolagus cuniculus) with an average weight of 3.0 kg. The animals were randomly divided into three groups: Group 1 – controls (5 animals), Group 2 – exposed to low-voltage current (8 animals), and Group 3 – exposed to high-voltage current (8 animals). Electrodes were placed on shaved areas on the right hind limb. Immediately after current application, animals were sacrificed using high doses of anesthetic. Next, sites of current application, femoral neurovascular bundles, femoral muscle samples (including its fascia), heart muscle samples, and abdominal aorta samples were collected for study. The samples were then processed for histological, histochemical, and immunohistochemical examination. Compared with the control group, no acute changes were found in the collected samples, except for the areas of current application where the thermal effect of current applications were observed. Post-current tissue damage described in the literature is not useful for immediate diagnosis. Diagnosis is often only possible after several tens of minutes to several hours, with observed tissue injury presumably resulting from electroporation or as part of tissue repair processes. We concluded that acute tissue changes after electric current injury are not specific except for heat-related skin and soft tissue changes at the point of electrocution.

Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers’ prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct \"non-intestinal\" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS . CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

Amyloid precursor protein (APP) plays an essential role in brain function and development. Variants in the APP gene are associated with both familial Alzheimer’s disease and cerebral amyloid angiopathy. We report a case of early onset, slowly progressive mixed dementia with a newly identified APP variant. The patient developed mild cognitive impairment at age 51, followed by neuropsychiatric symptoms, seizures, and progressive white matter changes. Despite a fluctuating clinical course, significant deterioration occurred later, culminating in death at age 77. Genetic testing revealed an APP c.2086G > A (p.Gly696Ser) variant, currently classified as a variant of uncertain significance (VUS). Postmortem examination showed definite AD neuropathologic changes, with fully blown amyloid pathology including amyloid deposits in plaques as well as in severe generalized cerebral angiopathy with concomitant advanced FTLD-tau pathology. In silico analysis of the variant’s impact was performed, and the inconclusive results are discussed later.

Colorectal carcinoma (CRC) is a disease that causes significant morbidity and mortality worldwide. To improve treatment, new biomarkers are needed to allow better patient risk stratification in terms of prognosis. This study aimed to clarify the prognostic significance of colonic-specific transcription factor special AT-rich sequence-binding protein 2 (SATB2), cytoskeletal protein cytokeratin 7 (CK7), and immune checkpoint molecule programmed death-ligand 1 (PD-L1). We analyzed a cohort of 285 patients with surgically treated CRC for quantitative associations among the three markers and five traditional prognostic indicators (i.e., tumor stage, histological grade, variant morphology, laterality, and mismatch-repair/MMR status). The results showed that loss of SATB2 expression had significant negative prognostic implications relative to overall survival (OS) and cancer-specific survival (CSS), significantly shortened 5 years OS and CSS and 10 years CSS in patients with CRC expressing CK7, and borderline insignificantly shortened OS in patients with PD-L1 + CRC. PD-L1 showed a significant negative impact in cases with strong expression (membranous staining in 50–100% of tumor cells). Loss of SATB2 was associated with CK7 expression, advanced tumor stage, mucinous or signet ring cell morphology, high grade, right-sided localization but was borderline insignificant relative to PD-L1 expression. CK7 expression was associated with high grade and SATB2 loss. Additionally, a separate analysis of 248 neoadjuvant therapy-naïve cases was performed with mostly similar results. The loss of SATB2 and CK7 expression were significant negative predictors in the multivariate analysis adjusted for associated parameters and patient age. In summary, loss of SATB2 expression and gain of CK7 and strong PD-L1 expression characterize an aggressive phenotype of CRC.

The understanding of neurodegenerative diseases, traditionally considered to be well-defined entities with distinguishable clinical phenotypes, has undergone a major shift over the last 20 years. The diagnosis of neurodegenerative diseases primarily requires functional brain imaging techniques or invasive tests such as lumbar puncture to assess cerebrospinal fluid. A new biological approach and research efforts, especially in vivo, have focused on biomarkers indicating underlying proteinopathy in cerebrospinal fluid and blood serum. However, due to the complexity and heterogeneity of neurodegenerative processes within the central nervous system and the large number of overlapping clinical diagnoses, identifying individual proteinopathies is relatively difficult and often not entirely accurate. For this reason, there is an urgent need to develop laboratory methods for identifying specific biomarkers, understand the molecular basis of neurodegenerative disorders and classify the quantifiable and readily available tools that can accelerate efforts to translate the knowledge into disease-modifying therapies that can improve and simplify the areas of differential diagnosis, as well as monitor the disease course with the aim of estimating the prognosis or evaluating the effects of treatment. The aim of this review is to summarize the current knowledge about clinically relevant biomarkers in different neurodegenerative diseases.

Pancreatic carcinoma remains one of the leading cancer-related causes of death worldwide and is generally characterized by a dismal prognosis and limited potential for oncologic treatment. A rare subvariant of pancreatic cancer, undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), has an unpredictable prognosis according to many previous studies, with unexpectedly long survival in individual cases. In this study, we collected, retrospectively, 13 cases of well-documented UCOGCs and performed immunohistochemistry focused on the expression of the programmed death-ligand 1 (PD-L1) and several other potential therapeutic and predictive markers (PanTRK, p53, MSH2, PMS2, and the number of tumor-infiltrating lymphocytes), to explore their correlation with the follow-up of the patients. As a control group, we examined 24 cases of conventional pancreatic ductal adenocarcinoma (PDAC). In our results, PanTRK was negative in all 24 cases. P53 did not show any significant differences between UCOGCs and PDACs, and the entire cohort was MSH2, MLH1, PMS2, and MSH6 positive. Significant differences were present in the analysis of PD-L1: UCOGCs were found to express PD-L1 significantly more frequently and have a higher number of tumor-infiltrating lymphocytes than PDAC. The expression of PD-L1 was related to significantly shorter survival in patients with UCOGC and in the entire cohort. Patients with PD-L1 negative UCOGCs displayed surprisingly long survival in comparison to PD-L1 positive UCOGCs and PDACs (both PD-L1+ and PD-L1−). We compared our results with previously published data, and, after statistical analysis, we were able to identify PD-L1 as an effective prognostic marker of UCOGC and suggest a strong need for a clinical trial of immune checkpoint immunotherapy in patients with advanced PD-L1 positive UCOGC.

Penile squamous cell carcinoma (pSCC) is a rare genitourinary tumor associated with notable psychosexual distress and poor prognosis. Traditional prognostic factors for pSCC include TNM stage and histological grade, with lymph node metastases being a critical indicator of poor prognosis. This study aimed to evaluate the prognostic impact of the following immunohistochemistry markers routinely used in histopathology practice: GATA3, IMP3, HIF-1-α, CK7, CA-IX, HER2, and TTF-1. A retrospective cohort of 145 patients with pSCC was analyzed using tissue microarray and immunohistochemical techniques. Overall survival (OS) was correlated statistically with detected marker expression. Key findings include that low GATA3 expression is associated with significantly worse OS in univariate Cox regression truncated at 3 years of follow-up. Low GATA3 retained prognostic impact when adjusted for major clinicopathological variables: Age, pT and pN stage, grade, lymphatic, venous, and perineural invasion, lymphocytic infiltrate, and expression of p16, p53, and PD-L1. Low GATA3 expression was associated with shorter cancer-specific survival (CSS) at 10 years follow-up. IMP3, CK7, and CA-IX showed statistically insignificant trends towards poorer prognosis. CK7 and CA-IX were more frequently expressed in high grade pSCC and in p16/HPV-positive tumors. IMP3 and CA-IX were associated with regional lymph node metastases. All cases were negative in TTF-1 and HER2. This study suggests GATA3 as a potential prognostic marker in pSCC.

We have evaluated the diagnostic potential of the seeding amplification assay (SAA) in detecting α-synuclein seeding activity in postmortem brain and cerebrospinal fluid (CSF) samples from patients with primary and co-pathology α-synucleinopathies. Moreover, we investigated potential SAA positivity in control samples which may suggest unrecognized co-pathology. A total of 15 brain and 14 CSF samples with definite dementia with Lewy bodies (DLB, n = 6), Alzheimer´s disease with amygdala Lewy body (AD/ALB, n = 3), and patients with concomitant Creutzfeldt-Jakob disease and Lewy body pathology (CJD/LBP, n = 6) comorbidity were tested for α-synuclein seeding activity using SAA assay utilizing recombinant α-synuclein (WT) with N-terminal His-tag. Control samples consisted of other neurodegenerative diseases (n = 17 for brain and n = 18 for CSF samples) and healthy corneal donors (n = 17). The analysis of seeding activity in brain samples suggested 100% sensitivity and 91.2% specificity. Five out of 34 brain control samples gave a positive SAA outcome. However, upon reevaluation, two of these samples were reclassified as Alzheimer´s disease (AD) with synucleinopathy co-pathology. The analysis of CSF also suggested 100% sensitivity and 94.4% specificity, although dilution of some samples was necessary to decrease the effect of inhibitors. We report a good performance of the SAA not only in postmortem samples from primary synucleinopathies with advanced pathology, but also in co-pathology synucleinopathies with isolated Lewy bodies in the amygdala in AD cases. Our findings highlight the importance of careful diagnostic evaluation in AD patients, where co-existing synucleinopathy may otherwise go unrecognized.

Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases´ diagnostics.